CN115190794A

CN115190794A - Pharmaceutical composition for controlling parasites on non-human organisms

Info

Publication number: CN115190794A
Application number: CN202180017552.1A
Authority: CN
Inventors: A·弗勒利希; A·特伯格; S·门宁格; D·格里契克; D·贡多; W·巴顿
Original assignee: Bayer Animal Health GmbH
Current assignee: Bayer Animal Health GmbH
Priority date: 2020-01-29
Filing date: 2021-01-27
Publication date: 2022-10-14
Also published as: AR122371A1; CA3169209A1; MX2022009240A; BR112022014802A2; US20230090439A1; EP4096626A1; AU2021214719A1; JP2023512012A; TW202142235A; WO2021151963A1

Abstract

The invention relates to a pharmaceutical composition comprising at least one pharmaceutical active ingredient which is completely dissolved in a solvent phase, characterized in that the pharmaceutical active ingredient is selected in particular from fluorinated heteroaryl amides, and the solvent phase is formulated as a solvent mixture and comprises at least one first solvent and a second solvent which is different from the first solvent, wherein the first solvent comprises a C1 to C15-alcohol, wherein the second solvent comprises an organic carbonate, and wherein the first solvent is present in a proportion of from 50% to 95% by weight and wherein the second solvent is present in a proportion of from 5% to 50% by weight, in each case based on the sum of the solvents in the solvent phase.

Description

Pharmaceutical composition for controlling parasites on non-human organisms

The present invention relates to pharmaceutical compositions for controlling parasites on non-human organisms. The invention relates in particular to dermopharmaceutical preparations having improved applicability to organisms, for the control of ectoparasites in mammals and domestic animals.

Modern fluorine-containing antiparasitic active compounds, also referred to as fluorinated antiparasitic agents, such as fluralanine (fluralaner), afurane (afoxolaner), sarolaner, lotilaner, fipronil (fipronil), which are known for a relatively long time, and the active ingredients described in WO2015/067646 and WO2015/067647 have good insecticidal and acaricidal properties. However, many of these active compounds suitable for topical administration to animals have very low solubility in solvents. To avoid dripping of the formulation from the coat or incomplete distribution on the animal skin after application, the active compound should preferably be dissolved in a small amount of solvent. Furthermore, the solvents must be toxicologically safe and have a high skin compatibility.

WO96/17520 relates to a formulation for transdermal administration to animals for controlling parasitic insects, having the following components: an agonist or antagonist of an insect nicotinic acetylcholine receptor at a concentration of 1 to 20% by weight, based on the total weight of the formulation; benzyl alcohol group or optionally pyrrolidone group, in a concentration of at least 20% by weight, based on the total weight of the formulation; optionally, an additional solvent selected from cyclic carbonates or lactones in a concentration of 5.0 to 80 weight percent, based on the total weight of the formulation; optionally, further auxiliaries selected from thickeners, spreading agents, dyes, antioxidants, foaming agents, preservatives, adhesives, emulsifiers, in concentrations of from 0.025 to 10% by weight, based on the total weight of the formulation.

Topical pour-on products against animal parasites are known, the formulation of which comprises isopropanol as solvent. These include in particular products containing the active ingredient ivermectin (ivermectin), for example

Pour-on

Pour-on

And the like. Examples of pour-on products comprising isopropanol and other active ingredients are:

Pour-on(

phoxim (Phoxim) as an active ingredient,

(Elanco, active ingredient: doramectin).

The object of the present invention is to provide a pharmaceutical composition for topical application to non-human organisms using solvents in which modern, for example fluorinated, antiparasitic agents (in particular from heteroaryl amides) have a sufficiently high solubility, while at the same time having good suitability for animals, in particular as a pour-on formulation.

A pharmaceutical composition is provided which comprises at least one parasiticidal pharmaceutically active ingredient and which is particularly easy to administer to an animal, is completely soluble in a solvent phase, wherein the pharmaceutically active ingredient is particularly selected from fluorinated heteroaryl amides, preferably pyridylamides, and wherein the solvent phase is configured as a solvent mixture and comprises a first solvent and a second solvent which is different from the first solvent, wherein the first solvent comprises a C1 to C15-alcohol, wherein the second solvent comprises an organic carbonate, and wherein the first solvent is present in a proportion of from 50% to 95% by weight, and wherein the second solvent is present in a proportion of from 5% to 50% by weight, in each case based on the sum of the solvents in the solvent phase.

For example, the quantitative ratio of the first solvent and the second solvent to each other may be 50% by weight: 50 to 95 wt%: 5% by weight, based on the sum of the solvents in the solvent phase.

According to another embodiment, the first solvent may comprise only one solvent or a combination of two or more, preferably a combination of two C1 to C15-alcohols, wherein in this configuration a majority of the C1 to C15-alcohols are present together in the above amounts and collectively referred to as first solvent. Thus, in the context of the present invention, a solvent is not necessarily to be understood as only one substance, but a solvent may also be understood as a mixture of different substances. However, it is to be noted that the substances forming the first solvent are all C1 to C15-alcohols.

Alternatively or additionally, provided that the second solvent consists of one substance or can be a combination of two or more, preferably two substances, wherein the substances forming the second solvent are both organic carbonates. In this configuration, two or more organic carbonates are present together in the amounts described above.

The solvent phase consisting of only the first solvent and the second solvent is also referred to as binary solvent phase.

The compositions of the invention are particularly capable of providing novel liquid medicaments for topical or dermal application to non-human organisms, using solvents in which, in particular, fluorinated antiparasitic agents selected from heteroaryl amides have sufficiently high solubility and at the same time good animal compatibility, in particular as pour-on formulations.

The pharmaceutical compositions described herein further comprise at least one pharmaceutically active ingredient, hereinafter also referred to as active ingredient, also referred to as API (active pharmaceutical ingredient). In particular, the active ingredient may be the actual active substance in the composition and thus produce mainly or totally an antiparasitic effect, as will be described in detail hereinafter. Therefore, the active ingredient should be particularly effective against non-human organisms.

In principle, the pharmaceutically active ingredient is not limited. Provided, however, that the pharmaceutically active ingredient consists in particular of a fluorinated heteroaryl amide, which is described in more detail below. In principle, the heteroaryl amide may be, for example, a pyridyl amide, which is a pyridine group bonded to the amide through an aryl group. For example, heteroaryl amides may be fluorinated.

With regard to the pharmaceutically active ingredient, it is also specified that it is completely dissolved in the solvent phase. This achieves in particular advantageous skin applications, wherein in particular pour-on applications or solutions for pour-on are possible.

Pour-on application, wherein the spot-on formulation may be an embodiment, is understood to mean in particular a type of application to a restricted skin area (usually in the neck or back of a non-human organism), wherein relatively small amounts of the formulation are applied, for example up to 100mL/100kg, about 1mL/100kg to 100mL/100kg, such as 1mL/100kg to 20mL/100kg, about 5mL/100kg to 10mL/100kg, based on the amount of the formulation applied to the weight of the organism. Thus, pour-on formulation is understood to mean a formulation of a kind that is suitable and intended for administration as a pour-on.

For such applications, i.e. in so-called pour-on solutions, it is particularly important to achieve a high solubility of the active ingredient, which enables the active ingredient in the solution to reach the desired concentration. Furthermore, good spreading properties on the skin should be achieved. Spreading characteristics are understood to mean, in particular, the distribution of the formulation on the skin. Thus, by means of the spreading properties, it can be determined whether the preparation in the form of a solution achieves the desired distribution on the organism, in particular without excessive dripping or running off from the site of application, so that locally limited application is possible and no loss of active ingredient occurs after application due to running off.

In order to achieve the abovementioned advantageous properties, in particular for pour-on formulations, it is intended in the compositions described herein to arrange the solvent phase as a solvent mixture and to comprise a first solvent and a second solvent which is different from the first solvent, wherein the first solvent comprises a C1 to C15-alcohol, wherein the second solvent is an organic carbonate, and wherein the first solvent is present in a proportion of from 50% to 95% by weight, and wherein the second solvent is present in a proportion of from 5% to 50% by weight, in each case based on the sum of the solvents in the solvent phase, wherein in the binary solvent phase the first solvent and the second solvent are present in a quantitative ratio to one another of 50% by weight: 50 to 95 wt%: 5 wt% is present based on the sum of the solvents in the solvent phase. It should be noted, however, that the sum of the proportions of the first and second solvents does not necessarily have to amount to 100% by weight, since, for example, ternary systems with other solvents are also conceivable and may be preferred.

In one embodiment, such a configuration may advantageously provide a sufficient concentration of fully dissolved heteroaryl amide active ingredient in the solvent phase, thus being possible in a formulation, and may also result in advantageous spreading characteristics for pour-on applications. In one embodiment, the active heteroaryl amide is at least 95% by weight (of the active ingredient) dissolved. In another embodiment, at least 97% by weight (of the active ingredient) of the active is dissolved. In yet another embodiment, 99% by weight of the active substance (of the active ingredient) is dissolved. In a preferred embodiment, 100% (by weight of the active ingredient) of the active substance is dissolved.

Thus, contrary to the assumptions made in the prior art, it has been shown that positive properties can be achieved using solvent mixtures comprising C1 to C15-alcohols (in particular C1-C10-alcohols, for example C1-C7-alcohols) and organic carbonates. For example, the solvent mixture may consist of one or more C1 to C15-alcohols and one or more organic carbonates. These combinations show, for example, good solubility of the active ingredients, in particular of the active ingredients formed from fluorinated heteroaryl amides, and good spreading characteristics.

C1-C15-alcohols are understood in principle to mean aliphatic or aromatic alcohols having from 1 to 15 carbon atoms.

Organic carbonates are also understood to mean acyclic or cyclic carbonates which are themselves low-volatility polar solvents and are characterized by their low toxicity. By skilled selection of the alcohol used for ester synthesis, the physical properties of the resulting carbonate can be tailored to the desired application area.

The present invention thus provides a composition which is well suited for pour-on administration, both in terms of spreading characteristics, ease of administration, and concentration of the active ingredient, i.e. efficacy.

Further advantages of the formulations described herein are good compatibility and safety with the organisms being treated, for example a reduction of harmful effects on the animal, for example harmful effects on the skin and/or coat, for example irritation or residues in the animal, including in animals entering the food chain. Formulation and ease of administration (good application due to viscosity and spreadability) provide excellent environmental sustainability, leading to high consumer acceptance and reduced deleterious side effects. This applies even in the case of livestock in food production. Furthermore, the formulation allows the active ingredient present to provide high efficacy in a shorter time through increased dissolved concentration, thereby being effective and thus providing a sustained active period without the need for frequent administration. Finally, good operability and user friendliness are achieved, while the cost of manufacturing the formulation is reduced. Also advantageous are good bioavailability and a range of uses.

Furthermore, the compositions of the invention can be easily administered to animals, for example taking into account viscosity and spreading characteristics. The composition, especially the active ingredient, also has a low tendency to be washed off, for example by rain. Indeed, efficacy can be maintained even in the case of wet animals or in the case of sun exposure. The compositions generally have high stability and exhibit reduced degradation and reduced secondary reactions of the composition components, such as with each other. Preferred stabilities achieved by the compositions described herein include a shelf life of at least 12 months, preferably 24 months, at 30 ℃. After application, the composition dries out easily, especially by the addition of good evaporating solvents, without significantly impairing the appearance of the animal.

For the solvents present in the solvent phase or solvent mixture, the following solvents are particularly advantageous. The first solvent is different from the second solvent. In one embodiment, the first solvent is not a carbonate, as opposed to the second solvent.

In one embodiment, the first solvent preferably comprises a C1-C4-alkanol optionally substituted by at least one C1-C4-alkoxy group or phenyl group, wherein the hydroxy group can in principle be in any alternative position. In a particular embodiment, the first solvent is selected from ethanol, n-propanol, isopropanol, butanol, e.g. isobutanol or n-butanol, especially ethanol and/or isopropanol. In addition to good solubility properties, especially in combination with the organic carbonates, such solvents offer the further advantage of suitable toxicity for non-human organisms, so that they can be administered in animals without adverse effects.

The second solvent is preferably an organic aliphatic C1-C4-carbonate, which is optionally substituted by hydroxyl groups. In a particular embodiment, the second solvent is selected from ethylene carbonate, propylene carbonate, glycerol carbonate. In addition to good dissolution characteristics, particularly in combination with the alcohol, such solvents also offer the additional advantage of suitable toxicity for non-human organisms, so that they can be administered in animals without adverse effects.

In a particularly preferred embodiment, the first solvent is isopropanol and the second solvent is propylene carbonate. It has been found that a solvent phase comprising isopropanol and propylene carbonate as solvents, for example, provides the advantages described above with respect to good solubility of the active ingredient, favorable spreading characteristics and at the same time lower toxicity.

In another embodiment, the solvent mixture consists of a first solvent (i.e., one or more first solvents as described above) and a second solvent (i.e., one or more second solvents as described above). In other words, the aforementioned first and second solvents may suffice as solvents only, wherein in an understandable manner one of the first solvents and one of the second solvents may suffice to form a solvent mixture.

In one embodiment, with respect to the relative proportions of the first solvent and the second solvent, it is preferred that the second solvent (i.e., the organic carbonate) is present in an amount of ≥ 20% by weight to ≤ 45% by weight, preferably ≥ 30% by weight to ≤ 40% by weight, based on the sum of the solvents in the solvent mixture. In this embodiment, the first solvent is present in an amount of ≥ 55% by weight to ≤ 80% by weight, preferably in an amount of ≥ 60% by weight to ≤ 70% by weight, based on the total amount of solvents in the solvent mixture. In this configuration, the above-mentioned advantages with respect to the solubility of the active ingredient can be provided particularly effectively, while having good spreading properties. In other words, with consistent results, excellent solubility of the active ingredient may be promoted. Thus, both advantageous applicability and stable storage characteristics are provided. Due to the high solubility of the active ingredient, relatively small amounts of solvent mixtures are required. As a result, the composition can be stored.

Further, in another embodiment, the solvent mixture comprises, in addition to the first solvent and the second solvent, a third solvent different from the first solvent and the second solvent. Thus, the third solvent is not designed as described above for the first and second solvents.

By using other solvents, the solubility and/or spreading characteristics can potentially be further improved or at least tailored to the desired use.

In a specific embodiment, the solvent phase is configured as a mixture of at least three solvents, wherein the third solvent is neither a C1 to C15-alcohol nor an organic carbonate, but has a definition different hereto. However, this does not exclude that the first solvent and/or the second solvent and/or the third solvent are present in each case, for example, as a binary solvent mixture.

In principle, by providing a ternary solvent phase, the first solvent and the second solvent may be present in the above-described ranges, wherein the ratio of the first solvent and the second solvent may comprise the ratio of the third solvent. In particular, in one embodiment, a third solvent replaces a part of the first solvent, wherein the first solvent is still present in the stated range from 50% to 95% by weight, based on the sum of the solvents in the solvent phase, and wherein the second solvent is likewise present in the stated amount range, i.e. in a proportion of from 5% to 50% by weight, in each case based on the sum of the solvents in the solvent phase. The third solvent, as well as the first and second solvents, should be pharmaceutically compatible and also not adversely affect the solubility of the active ingredient. It may be advantageous to use a permeation enhancing solvent.

Advantageous examples of third solvents different from the first and second solvents are selected from water, butylhydroxytoluene, N-methylpyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, triethyl phosphate, benzyl benzoate, octyldodecanol, paraffins, triglycerides, such as caprylic/capric triglyceride (e.g., miglyol 812), propylene glycol caprylic decanoate (e.g., miglyol 840), glycol ethers such as diethylene glycol methyl ether, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether, diethylene glycol monobutyl ether.

In one embodiment, the solvent phase may be a ternary system and thus consists of a first solvent or solvents, a second solvent or solvents and a third solvent or solvents. In this embodiment, the first solvent(s), the second solvent(s), and the third solvent(s) may be selected as defined above.

In particular, in the embodiment of the ternary system, one non-limiting example is the sum of the first and third solvents and the second solvent in a quantitative ratio to each other of 50% by weight to 95% by weight: 5% by weight, based on the sum of the solvents in the solvent phase. With respect to the relative proportions of the first solvent and the second solvent, it is preferred that the second solvent is present in an amount of ≥ 20% by weight to ≤ 45% by weight, preferably in an amount of ≥ 30% by weight to ≤ 40% by weight, based on the sum of the solvents in the solvent mixture. Thus, the first solvent and the optional third solvent may be present together in a content of ≥ 55% by weight to ≤ 80% by weight, preferably in a content of ≥ 60% by weight to ≤ 70% by weight, based on the sum of the solvents in the solvent mixture.

Non-limiting examples of solvent mixtures can be configured, for example, as follows: mixtures of isopropanol (32.5), ethanol (32.5) and propylene carbonate (35) can be used, wherein the figures in brackets mean the content in% by weight, based on the solvent mixture. As further examples, isopropanol (32.5), ethanol (32.5) and glycerol carbonate (35), isopropanol (65), mixtures of propylene carbonate (17.5) and glycerol carbonate (17.5) or mixtures of ethanol (65), propylene carbonate (17.5) and glycerol carbonate (17.5) can be used, wherein the numbers in brackets again refer to the content in% by weight, based on the solvent mixture.

In one embodiment, there is a first solvent and a solvent mixture consisting of, for example, two second solvents and optionally one or more third solvents. In another embodiment, there is a second solvent and a solvent mixture consisting of, for example, two first solvents and optionally one or more third solvents.

Furthermore, the ingredients of the composition may be limited to the solvent and the active ingredient, such that the composition may consist of the first solvent, the second solvent, the optional third solvent, and the active ingredient. However, other ingredients are not intended to be excluded and are defined elsewhere.

Preferably, the fluorinated heteroaryl amide is designed as described in WO 2015067646 A1 or WO 2015067647 A1. Such active ingredients are preferably configured as follows and comprise compounds of the general formula (I), as well as salts, N-oxides and tautomeric forms of the compounds of the formula (I):

wherein

R ¹ Is H; c optionally substituted in each case ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₆ -alkylcarbonyl, C ₁ -C ₆ Alkoxycarbonyl, aryl- (C) ₁ -C ₃ ) -alkyl, heteroaryl- (C) ₁ -C ₃ ) -an alkyl group; or optionally substitutedC ₁ -C ₆ -alkyl, preferably H or preferably C ₁ -C ₂ Alkyl, very particularly preferably H or methyl, in particular H,

these parts are as follows:

A ₁ is CR ² Or the number of N is greater than the number of N,

A ₂ is CR ³ Or the number of the N-substituted aryl groups,

A ₃ is CR ⁴ Or the number of N is greater than the number of N,

A ₄ is CR ⁵ Or the number of N is greater than the number of N,

B ₁ is CR ⁶ Or the number of the N-substituted aryl groups,

B ₂ is CR ⁷ Or the number of the N-substituted aryl groups,

B ₃ is CR ⁸ Or the number of N is greater than the number of N,

B ₄ is CR ⁹ Or N, and

B ₅ is CR ¹⁰ Or the number of the N-substituted aryl groups,

but not more than three A ₁ To A ₄ Part is N and not more than three B ₁ To B ₅ Part is N;

R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁹ and R ¹⁰ Each independently of the others being H, halogen, cyano, nitro, in each case optionally substituted C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₆ Alkoxy, N-C ₁ -C ₆ -alkoxyimino-C ₁ -C ₃ Alkyl radical, C ₁ -C ₆ Alkyl sulfanyl, C ₁ -C ₆ -alkylsulfinyl, C ₁ -C ₆ -alkylsulfonyl, N-C ₁ -C ₆ Alkylamino, N-di-C ₁ -C ₆ Alkylamino or N-C ₁ -C ₃ -alkoxy-C ₁ -C ₄ -alkylamino or 1-pyrrolidinyl; if A is ₂ And A ₃ All moieties are not N, then R ³ And R ⁴ May form, together with the carbon atom to which they are bonded, a 5-or 6-membered ring containing 0, 1 or 2 nitrogen atoms and/or 0 or 1 oxygen atom and/or 0 or 1 sulfur atom; or if A ₁ And A ₂ All moieties are not N, then R ² And R ³ May form together with the carbon atom to which they are bonded a 6-membered ring containing 0, 1 or 2 nitrogen atoms;

R ⁸ is halogen, cyano, nitro; c optionally substituted in each case ₁ -C ₆ Alkyl radical, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₆ Alkoxy, N-C ₁ -C ₆ -alkoxyimino-C ₁ -C ₃ Alkyl radical, C ₁ -C ₆ Alkyl sulfanyl, C ₁ -C ₆ -alkylsulfinyl, C ₁ -C ₆ -alkylsulfonyl, N-C ₁ -C ₆ Alkylamino or N, N-di-C ₁ -C ₆ -an alkylamino group;

w is O or S, and W is O or S,

q is H, formyl, hydroxy, amino or in each case optionally substituted C ₁ -C ₆ -an alkyl group; c ₂ -C ₆ -an alkenyl group; c ₂ -C ₆ -an alkynyl group; c ₃ -C ₆ -a cycloalkyl group; c ₁ -C ₅ -a heterocycloalkyl group; c ₁ -C ₄ -an alkoxy group; c ₁ -C ₆ -alkyl-C ₃ -C ₆ -a cycloalkyl group; c ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -an alkyl group; c ₆ 、C ₁₀ -C ₁₄ -an aryl group; c ₁ -C ₅ -a heteroaryl group; c ₆ -、C ₁₀ -、C ₁₄ -aryl- (C) ₁ -C ₃ ) -an alkyl group; c ₁ -C ₅ -heteroaryl- (C) ₁ -C ₃ ) -an alkyl group; N-C ₁ -C ₄ -an alkylamino group; N-C ₁ -C ₄ -alkylcarbonylamino or N, N-di-C ₁ -C ₄ -an alkylamino group; or is an optionally poly-V-substituted unsaturated 6-membered carbocyclic ring; or an optionally poly-V-substituted unsaturated 4-, 5-or 6-membered heterocyclic ring, wherein

V is independently of one another halogen, cyano, nitro; c optionally substituted in each case ₁ -C ₆ Alkyl radical, C ₁ -C ₄ -alkenyl, C ₁ -C ₄ -alkynyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₆ Alkoxy, N-C ₁ -C ₆ -alkoxyimino-C ₁ -C ₃ Alkyl radical, C ₁ -C ₆ Alkyl sulfanyl, C ₁ -C ₆ -alkylsulfinyl, C ₁ -C ₆ -alkylsulfonyl or N, N-di- (C) ₁ -C ₆ -alkyl) amino;

t is an optionally substituted 5-membered heteroaromatic system containing no more than 2 heteroatoms (1 or 2 heteroatoms), such as four carbon atoms and one (1) heteroatom, preferably one (1) nitrogen atom, one (1) oxygen atom or one (1) sulfur atom; or three carbon atoms and two heteroatoms, preferably two nitrogen atoms, one (1) nitrogen atom and one (1) oxygen atom, or one (1) nitrogen atom and one (1) sulfur atom.

For example, compounds of formula (Ia) and salts, N-oxides and tautomeric forms of compounds of formula (I) are described below:

wherein

D ₁ 、D ₂ Each moiety being independently of the other C-R ¹¹ Or a heteroatom selected from N and O;

D ₃ and D ₄ The moieties are independently of each other C or represent a heteroatom selected from N (in other words:

D ₃ and D ₄ Moieties independently of one another represent C or N);

wherein is selected from D ₁ 、D ₂ 、D ₃ And D ₄ No more than one (1) or two of the moieties are heteroatoms selected from D ₁ 、D ₂ 、D ₃ And D ₄ One (1) or two of the moieties being a heteroatom at D ₁ And D ₂ In the case of (B) is selected from N or O, or in D ₃ And D ₄ Is selected from N;

is an aromatic system; and

R ¹ 、A ₁ 、A ₂ 、A ₃ 、A ₄ 、B ₁ 、B ₂ 、B ₃ 、B ₄ 、B ₅ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ w, Q, V and T are each as defined herein, wherein is selected from A _l 、A ₂ 、A ₃ 、A ₄ No more than one of the moieties is N and is selected from B ₁ 、B ₂ 、B ₃ 、B ₄ And B ₅ No more than one of the moieties is N; or wherein is selected from A ₁ 、A ₂ 、A ₃ 、A ₄ One or two moieties of (A) may be N and selected from B ₁ 、B ₂ 、B ₃ 、B ₄ And B ₅ Is not more than one part of N

One embodiment of the present invention relates to compounds of formula (Ia

Wherein

R ¹ 、R ¹¹ 、Q、W、A ₁ 、A ₂ 、A ₃ 、A ₄ 、B ₁ 、B ₂ 、B ₄ And B ₅ Each is defined as described herein, wherein is selected from A ₁ 、A ₂ 、A ₃ 、A ₄ Is not more than one moiety N and is selected from B ₁ 、B ₂ 、B ₃ 、B ₄ And B ₅ Is N; or wherein is selected from A ₁ 、A ₂ 、A ₃ 、A ₄ One or two of the moieties may be N and selected from B ₁ 、B ₂ 、B ₃ 、B ₄ And B ₅ No more than one of the moieties is N;

D ₁ and D ₂ Each independently of the other is C-R ¹¹ Or hetero atoms, preferably C-R ¹¹ Or a heteroatom selected from N, O or S, more preferably C-R ¹¹ Or a heteroatom selected from N or O;

D ₃ and D ₄ The moieties are independently of each other C or a heteroatom selected from N;

wherein is selected from D ₁ 、D ₂ 、D ₃ And D ₄ No more than one (1) or two of the moieties are heteroatoms selected from D ₁ 、D ₂ 、D ₃ And D ₄ One or two of the moieties being hetero atoms, in D ₁ And D ₂ In the case of (A) is selected from N or O, or in D ₃ And D ₄ Is selected from the group consisting of N;

is an aromatic system, and is characterized in that,

R ⁸ as defined herein, is preferably perfluorinated C ₁ -C ₄ -an alkyl group.

Another embodiment of the invention relates to compounds of the formula (Ia ') and to salts, N-oxides and tautomeric forms of the compounds of the formula (Ia')

Wherein

D ₁ Is C-R ¹¹ Or a heteroatom selected from N or O;

D ₂ is C-R ¹¹ Or a heteroatom selected from N or O;

D ₃ is C or N;

D ₄ is C or N;

D ₅ is C-R ¹¹ Or N;

wherein is selected from D ₁ 、D ₂ 、D ₃ 、D ₄ And D ₅ No more than one (1) or two of the moieties are heteroatoms;

is fragrantA family system; and

R ¹ is H, in each case optionally substituted C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₆ -alkylcarbonyl group, C ₁ -C ₆ Alkoxycarbonyl, aryl- (C) ₁ -C ₃ ) -alkyl or heteroaryl- (C) ₁ -C ₃ ) -alkyl or optionally substituted C ₁ -C ₆ -alkyl, particularly preferably H;

these sections are as follows:

A ₁ is CR ² Or the number of the N-substituted aryl groups,

A ₂ is CR ³ Or the number of N is greater than the number of N,

A ₃ is CR ⁴ Or the number of N is greater than the number of N,

A ₄ is CR ⁵ Or the number of the N-substituted aryl groups,

B ₁ is CR ⁶ Or the number of the N-substituted aryl groups,

B ₂ is CR ⁷ Or the number of the N-substituted aryl groups,

B ₃ is CR ⁸ Or the number of N is greater than the number of N,

B ₄ is CR ⁹ Or N, and

B ₅ is CR ¹⁰ Or the number of N is greater than the number of N,

but A is ₁ To A ₄ No more than three of the moieties are N, and B ₁ To B ₅ No more than three of the portions are simultaneously N; r is ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁹ And R ¹⁰ Each independently of the others being H, halogen, cyano

Radical, nitro, in each case optionally substituted C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₆ Alkoxy, N-C ₁ -C ₆ -alkoxyimino-C ₁ -C ₃ Alkyl radical, C ₁ -C ₆ Alkyl sulfanyl, C ₁ -C ₆ -alkylsulfinyl, C ₁ -C ₆ -alkylsulfonyl, N-C ₁ -C ₆ Alkylamino or N, N-di-C ₁ -C ₆ -an alkylamino group; such asFruit A ₂ And A ₃ All moieties are not N, then R ³ And R ⁴ May form, together with the carbon atom to which they are bonded, a 5-or 6-membered ring containing 0, 1 or 2 nitrogen atoms and/or 0 or 1 oxygen atom and/or 0 or 1 sulfur atom; or if A is ₁ And A ₂ All moieties are not N, then R ² And R ³ May form together with the carbon atom to which they are bonded a 6-membered ring containing 0, 1 or 2 nitrogen atoms;

R ⁸ halogen, cyano, nitro; c optionally substituted in each case ₁ -C ₆ Alkyl radical, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₆ Alkoxy, N-C ₁ -C ₆ -alkoxyimino-C ₁ -C ₃ Alkyl radical, C ₁ -C ₆ Alkyl sulfanyl, C ₁ -C ₆ -alkylsulfinyl, C ₁ -C ₆ -alkylsulfonyl, N-C ₁ -C ₆ Alkylamino or N, N-di-C ₁ -C ₆ -an alkylamino group;

R ¹¹ independently of one another, H, halogen, cyano, nitro, amino or optionally substituted C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylcarbonyl group, C ₁ -C ₆ Alkyl sulfanyl, C ₁ -C ₆ -alkylsulfinyl, C ₁ -C ₆ -alkylsulfonyl, preferably H;

w is O or S, and W is O or S,

V is independently of one another halogen, cyano, nitro; c optionally substituted in each case ₁ -C ₆ Alkyl radical, C ₁ -C ₄ -alkenyl, C ₁ -C ₄ -alkynyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₆ Alkoxy, N-C ₁ -C ₆ -alkoxyimino-C ₁ -C ₃ Alkyl radical, C ₁ -C ₆ Alkyl sulfanyl, C ₁ -C ₆ -alkylsulfinyl, C ₁ -C ₆ -alkylsulfonyl or N, N-di- (C) ₁ -C ₆ -alkyl) amino.

Also suitable are compounds of formula (Ia '), wherein the compound of formula (Ia') is a compound of formula (I-T3)

Wherein R is ¹ 、A ₁ 、A ₂ 、A ₃ 、A ₄ 、R ¹¹ 、B ₁ 、B ₂ 、B ₄ 、B ₅ 、R ⁸ Q and W are each defined as described herein, wherein is selected from A ₁ 、A ₂ 、A ₃ 、A ₄ Is not more than one moiety N and is selected from B ₁ 、B ₂ 、B ₃ 、B ₄ And B ₅ Is N; or wherein is selected from A ₁ 、A ₂ 、A ₃ 、A ₄ One or two moieties of (A) may be N and selected from B ₁ 、B ₂ 、B ₃ 、B ₄ And B ₅ Is N.

Another embodiment of the present invention relates to compounds of formula (Ia '), wherein the compound of formula (Ia') is a compound of formula (I-T2)

Wherein R is ¹ 、A ₁ 、A ₂ 、A ₃ 、A ₄ 、R ¹¹ 、B ₁ 、B ₂ 、B ₄ 、B ₅ 、R ⁸ Q and W are each defined as described herein, wherein is selected from A ₁ 、A ₂ 、A ₃ 、A ₄ Is N and is selected from B ₁ 、B ₂ 、B ₃ 、B ₄ And B ₅ Is N; or wherein is selected from A ₁ 、A ₂ 、A ₃ 、A ₄ One or two moieties of (A) may be N and selected from B ₁ 、B ₂ 、B ₃ 、B ₄ And B ₅ Is N.

Another embodiment of the present invention relates to compounds of formula (Ia '), wherein the compound of formula (Ia') is a compound of formula (I-T4)

Wherein R is ¹ 、A ₁ 、A ₂ 、A ₃ 、A ₄ 、R ¹¹ 、B ₁ 、B ₂ 、B ₄ 、B ₅ R8, Q and W are each as defined herein, wherein is selected from A ₁ 、A ₂ 、A ₃ 、A ₄ Is not more than one moiety N and is selected from B ₁ 、B ₂ 、B ₃ 、B ₄ And B ₅ Is N; or wherein is selected from A ₁ 、A ₂ 、A ₃ 、A ₄ One or two moieties of (A) may be N and selected from B ₁ 、B ₂ 、B ₃ 、B ₄ And B ₅ Is N.

Also suitable are compounds of formula (Ia '), wherein the compound of formula (Ia') is a compound of formula (I-T22)

Also suitable are compounds of formula (Ia '), wherein the compound of formula (Ia') is a compound of formula (I-T23)

Wherein R is ¹ 、A ₁ 、A ₂ 、A ₃ 、A ₄ 、R ¹¹ 、B ₁ 、B ₂ 、B ₄ 、B ₅ 、R ⁸ Q and W are each defined as described herein, wherein is selected from A ₁ 、A ₂ 、A ₃ 、A ₄ Is N and is selected from B ₁ 、B ₂ 、B ₃ 、B ₄ And B ₅ Is N; or wherein is selected from A ₁ 、A ₂ 、A ₃ 、A ₄ One or two moieties of (A) may be N and selected from B ₁ 、B ₂ 、B ₃ 、B ₄ And B ₅ Not more than one part of isN。

Also suitable are compounds of the formulae and embodiments described herein, wherein R is ¹¹ Is H and W is O.

Also suitable are compounds of the formulae and embodiments described herein, wherein R is ¹¹ Is H and W is O and B ₃ Is C-R ⁸ ，R ⁸ Is halogen-substituted C ₁ -C ₃ Alkyl (preferably perhalogenated C) ₁ -C ₃ -alkyl, more preferably perfluorinated C ₁ -C ₃ -alkyl) or halogen substituted C ₁ -C ₃ Alkoxy (preferably perhalogenated C) ₁ -C ₃ Alkoxy, more preferably perfluorinated C ₁ -C ₃ -alkoxy groups).

Also suitable are compounds of the formulae and embodiments described herein, wherein a is ₁ To A ₄ And B ₁ To B ₅ The parts are as follows:

A ₁ is a compound of the formula C-H,

A ₂ is CR ³ Or the number of N is greater than the number of N,

A ₃ is CR ⁴ ，

A ₄ Is a compound of the formula C-H,

B ₁ is CR ⁶ Or the number of N is greater than the number of N,

B ₂ is a compound of the formula C-H,

B ₃ is CR ⁸ ，

B ₄ Is C-H and

B ₅ is CR ¹⁰ Or N.

Also suitable are compounds of the formulae and embodiments described herein, wherein R is ¹ Is H.

Also suitable are compounds of the formulae and embodiments described herein, wherein Q is fluoro substituted C ₁ -C ₄ Alkyl radical, C ₃ -C ₄ Cycloalkyl, optionally cyano or fluoro substituted C ₃ -C ₄ -cycloalkyl, C ₄ -C ₆ Heterocycloalkyl, 1-thiooxetan-3-yl, 1-thiooxetan-3-yl, benzyl, pyridin-2-ylmethyl, methylsulfonyl or 2-oxo-2- (2, 2-trifluoroethyl)Amino) ethyl.

More suitable are compounds of the formulae and embodiments described herein, wherein R is ⁸ Represents halogen or halogen-substituted C ₁ -C ₄ An alkyl group.

Also suitable are compounds of the formulae described herein, wherein R is ¹¹ Is H.

Also suitable are compounds of the formulae described herein, wherein R is ⁶ 、R ⁷ 、R ⁹ And R ¹⁰ Independently of one another, H, halogen, cyano, nitro, in each case optionally substituted C ₁ -C ₄ Alkyl radical, C ₃ -C ₄ -cycloalkyl, C ₁ -C ₄ Alkoxy, N-alkoxyiminoalkyl, C ₁ -C ₄ Alkyl sulfanyl, C ₁ -C ₄ -alkylsulfinyl, C ₁ -C ₄ -alkylsulfonyl, N-C ₁ -C ₄ Alkylamino, N-di-C ₁ -C ₄ -an alkylamino group.

Also suitable are compounds of the formulae described herein, wherein R is ² 、R ³ 、R ⁴ And R ⁵ Independently of one another, H, halogen, cyano, nitro, in each case optionally substituted C ₁ -C ₄ Alkyl radical, C ₃ -C ₄ -cycloalkyl, C ₁ -C ₄ Alkoxy, N-C ₁ -C ₄ -alkoxyimino-C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Alkyl sulfanyl, C ₁ -C ₄ -alkylsulfinyl, C ₁ -C ₄ -alkylsulfonyl, N-C ₁ -C ₄ Alkylamino or N, N-di-C ₁ -C ₄ -an alkylamino group.

Also suitable are compounds of the formulae described herein, wherein A ₁ To A ₄ And B ₁ To B ₅ The parts are as follows:

A ₁ is a compound of the formula C-H,

A ₂ is CR ³ Or the number of the N-substituted aryl groups,

A ₃ is CR ⁴ ，

A ₄ Is a compound of the formula C-H,

B ₁ is CR ⁶ Or the number of N is greater than the number of N,

B ₂ is a compound of the formula C-H,

B ₃ is CR ⁸ ，

B ₄ Is C-H and

B ₅ is CR ¹⁰ Or N.

Also suitable are compounds of the formulae described herein, wherein R is ¹ Is H.

Also suitable are compounds of the formulae described herein, wherein R is ¹ Is methyl.

Also suitable are compounds of the formulae described herein, where Q is fluorine-substituted or a carboxamide (-C (= O) N (R) ₂ Wherein R is independently of each other H, C ₁ -C ₃ -alkyl or halogen substituted C ₁ -C ₃ -alkyl) -substituted C ₁ -C ₄ -alkyl, optionally cyano or fluoro substituted C ₃ -C ₄ -cycloalkyl, C ₄ -C ₆ -heterocycloalkyl, 1-thioheterocyclicbut-3-yl, 1-thioheterocyclicbut-3-yl, benzyl, pyridin-2-ylmethyl, methylsulfonyl or 2-oxo-2- (2, 2-trifluoroethylamino) ethyl.

Also suitable are compounds of the formulae described herein, wherein Q is 2, 2-trifluoroethyl, 2-difluoroethyl, 3-trifluoropropyl, cyclopropyl, cyclobutyl, 1-cyanocyclopropyl, trans-2-fluorocyclopropyl, or cis-2-fluorocyclopropyl, oxetan-3-yl, thiedin-3-yl, 1-thiedin-3-yl, 1-thiedin-3-yl, benzyl, pyridin-2-ylmethyl, methanesulfonyl or 2-oxo-2- (2, 2-trifluoroethylamino) ethyl.

Also suitable are compounds of the formulae described herein, wherein R is ⁸ Is halogen or halogen-substituted C ₁ -C ₄ -an alkyl group.

Mention may be made, as examples, of the following, which are preferred as active ingredients having a parasiticidal effect on non-human organisms:

2-chloro-N-cyclopropyl-5- [1- [2, 6-dichloro-4- [1, 2-tetrafluoro-1- (trifluoromethyl) -ethyl ] phenyl ] pyrazol-4-yl ] -N-methylpyridine-3-carboxamide

2-chloro-N-cyclopropyl-5- [1- [ 2-chloro-4- [1, 2-tetrafluoro-1- (trifluoromethyl) ethyl ] -6- (trifluoromethoxy) phenyl ] -1H-pyrazol-4-yl ] -3-pyridinecarboxamide:

2-chloro-5- [1- [ 2-chloro-4- [1, 2-tetrafluoro-1- (trifluoromethyl) ethyl ] -6- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl ] -N-cyclopropyl-3-pyridinecarboxamide:

2-chloro-5- [1- [ 2-bromo-4- [1, 2-tetrafluoro-1- (trifluoromethyl) ethyl ] -6- (trifluoromethoxy) phenyl ] -1H-pyrazol-4-yl ] -N-cyclopropylpyridine-3-carboxamide

2-chloro-N-cyclopropyl-5- [1- [2, 6-dichloro-4- [1, 2-tetrafluoro-1- (trifluoromethyl) ethyl ] phenyl ] pyrazol-4-yl ] pyridine-3-carboxamide

2-chloro-N-cyanocyclopropyl-5- [1- [ 2-chloro-4- [1, 2-tetrafluoro-1- (trifluoromethyl) ethyl ] -6- (trifluoromethoxy) phenyl ] -1H-pyrazol-4-yl ] benzamide:

2-chloro-5- [1- [ 2-chloro-4- [1, 2-tetrafluoro-1- (trifluoromethyl) ethyl ] -6- (trifluoromethoxy) phenyl ] pyrazol-4-yl ] -N-cyclopropylbenzamide

5- [1- [ 2-bromo-4- [1, 2-tetrafluoro-1- (trifluoromethyl) ethyl ] -6- (trifluoromethoxy) phenyl ] pyrazol-4-yl ] -2-chloro-N-cyclopropylbenzamide

2-chloro-5- [1- [ 2-chloro-4- [1, 2-tetrafluoro-1- (trifluoromethyl) ethyl ] -6- (trifluoromethyl) phenyl ] pyrazol-4-yl ] -N-cyclopropylbenzamide

2-chloro-N-cyclopropyl-5- [1- [2, 6-dichloro-4- [1, 2-tetrafluoro-1- (trifluoromethyl) ethyl ] phenyl ] pyrazol-4-yl ] benzamide

2-chloro-N-cyclopropyl-5- [1- [2, 6-dichloro-4- [1, 2-tetrafluoro-1- (trifluoromethyl) ethyl ] phenyl ] pyrazol-4-yl ] -N-methylbenzamide

2-chloro-N-cyclopropyl-5- [1- [4- (1, 2, 3-heptafluoropropan-2-yl) -2-methyl-6- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl ] benzamide:

2-chloro-N- (1-cyanocyclopropyl) -5- [1- [4- (1, 2, 3-heptafluoropropan-2-yl) -2-methyl-6- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl ] benzamide:

2-chloro-N-cyclopropyl-5- [4- [2, 6-dimethyl-4- [1, 2-tetrafluoro-1- (trifluoromethyl) ethyl ] phenyl ] pyrazol-1-yl ] benzamide:

2-chloro-N- (1-cyanocyclopropyl) -5- [4- [2, 6-dichloro-4- [1, 2-tetrafluoro-1- (trifluoromethyl) ethyl ] phenyl ] pyrazol-1-yl ] benzamide:

2-chloro-5- [3- [ 2-chloro-4- [1, 2-tetrafluoro-1- (trifluoromethyl) ethyl ] -6- (trifluoromethyl) phenyl ] isoxazol-5-yl ] -N-cyclopropylbenzamide:

2-chloro-N- (1-cyanocyclopropyl) -5- [3- [ 2-methyl-4- [1, 2-tetrafluoro-1- (trifluoromethyl) ethyl ] -6- (trifluoromethyl) phenyl ] isoxazol-5-yl ] benzamide:

2-chloro-N- (1-cyanocyclopropyl) -5- [1- [2, 6-dichloro-4- [1, 2-tetrafluoro-1- (trifluoromethyl) ethyl ] phenyl ] pyrrol-3-yl ] benzamide:

2-chloro-5- [3- [ 2-chloro-4- [1, 2-tetrafluoro-1- (trifluoromethyl) ethyl ] -6- (trifluoromethyl) phenyl ] pyrrol-1-yl ] -N-cyclopropylbenzamide:

in this case, the above active ingredients are part of the formulations described herein and are therefore capable of achieving the efficacy against parasites as described in detail below.

In the context of the present invention, preference may be given to active ingredients of the formulae I-1 to I-5 and active ingredients of the formulae II-1 to II-6 described above, with active ingredients of the formulae I-1 to I-5 being particularly preferred.

According to a preferred embodiment, the compounds of formula I-1 can be present as active ingredients, wherein the following mixtures can be used as solvent mixtures: a mixture of isopropanol (32.5), ethanol (32.5) and propylene carbonate (35); or a mixture of isopropanol (32.5), ethanol (32.5) and glycerol carbonate (35); or a mixture of isopropanol (65), propylene carbonate (17.5) and glycerol carbonate (17.5); and mixtures of ethanol (65), propylene carbonate (17.5) and glycerol carbonate (17.5), wherein the values in brackets are intended to indicate the content in weight percent based on the solvent mixture.

According to another embodiment, the above-mentioned solvent mixtures can be used for the active ingredients of formula I-2 or formula I-3 or formula I-4 or formula I-5.

However, it is particularly preferred to use active ingredients of the formulae I-1, I-2, I-3, I-4 and I-5 in only the first and second solvents.

In addition to the ingredients listed above, the compositions of the present invention may also contain conventional pharmaceutically acceptable adjuvants. Examples of these that may be mentioned are: dispersants, antioxidants, pH adjusters, crystallization inhibitors, surfactants, dyes, pigments, permeation enhancers, and preservatives.

Dispersants are, for example, dispersing oils, such as di-2-ethylhexyl adipate, isopropyl myristate, dipropylene glycol nonanoate; cyclic and acyclic silicone oils such as polydimethylsiloxane and their copolymers and terpolymers with ethylene oxide, propylene oxide and formalin; fatty acid esters, triglycerides, fatty alcohols. They may be additionally added in a proportion of not less than 1-not more than 40% w/v. According to other embodiments, the dispersant may be present in a proportion of ≥ 0.01- ≦ 1% w/v, ≥ 0.1- ≦ 10% w/v, ≥ 1- ≦ 20% w/v, ≥ 20- ≦ 50% w/v or ≥ 10- ≦ 30% w/v.

Antioxidants are, for example, ascorbic acid, di-Na-EDTA, BHT, BHA, delta-tocopherol, thioglycerol. They may be additionally added in a proportion of 0.01-2% by weight. According to other embodiments, the antioxidant may be present in a proportion of ≥ 0.01- ≦ 1% w/v, ≥ 0.05- ≦ 0.5% w/v or ≥ 1- ≦ 2% w/v.

The pH adjusting agent is preferably an organic acid or base, such as citric acid, triethanolamine. They may be added separately in a proportion of 0.001-5% by weight or more. According to other embodiments, the pH adjusting agent can be present in a ratio of ≥ 0.01- ≦ 1% w/v, ≥ 0.05- ≦ 0.5% w/v or ≥ 0.1- ≦ 3% w/v.

Crystallization inhibitors are for example cellulose ethers, such as Hydroxypropylmethylcellulose (HPMC); polyvinylpyrrolidone (PVP). They may be additionally added in a proportion of ≥ 0.1- ≦ 50% w/v. According to other embodiments, the crystallization inhibitor may be present in a proportion of ≥ 1- ≦ 30 w/v, ≥ 1- ≦ 20 w/v, ≥ 5- ≦ 15 w/v, ≥ 1- ≦ 20% w/v or ≥ 0.1- ≦ 10% w/v.

Surfactants which may be mentioned are: nonionic surfactants such as polyoxyethylene castor oil, polyoxyethylene sorbitan monooleate, sorbitan monostearate, glyceryl monostearate, polyoxyethylene stearate, alkylphenol polyglycol ethers; amphoteric surfactants, such as di-Na-N-lauryl β -iminodipropionate or lecithin; anionic surfactants such as sodium lauryl sulfate, fatty alcohol ether sulfates, mono/dialkyl polyglycol ether orthophosphate monoethanol amine salts, and the like; cationic active surfactants such as cetyltrimethylammonium chloride. They may be additionally added in a proportion of ≥ 0.1 ≤ 20% w/v. According to other embodiments, they may be present in a proportion of ≧ 0.1- ≦ 10% w/v, ≧ 0.1- ≦ 1% w/v,% 1- ≦ 10% w/v or ≦ 0.2- ≦ 5% w/v.

Dyes may also be added to the pharmaceutical composition. They may be dissolved or suspended in the composition. Examples which may be mentioned are brilliant blue, D & C violet No. 2, FD & C yellow, sunset yellow FCF or natural food pigments such as chlorophyll. They may be additionally added in a proportion of not less than 0.01- ≦ 2% w/v. According to other embodiments, they may be present in a proportion of ≥ 0.01- ≦ 1% w/v or ≥ 0.1- ≦ 2% w/v.

The pharmaceutical composition may contain penetration enhancers such as: menthol, 1, 8-cineole, glycol ethers (e.g., diethylene glycol methyl ether, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether, diethylene glycol monobutyl ether). They may be present in a proportion of ≥ 2-50% w/v. According to other embodiments, the penetration enhancer may be present in a proportion of ≥ 1- ≦ 20 w/v, ≥ 0.5- ≦ 20 w/v, ≥ 0.1- ≦ 10% w/v, ≥ 10- ≦ 50% w/v or ≥ 10- ≦ 40% w/v.

In principle, the concentration of the active ingredient is not limited, but the fact that all active ingredients should be in solution should also be taken into account. With respect to advantageous pour-on administration, it may also be preferred for high efficacy that the pharmaceutically active ingredient is present in an amount of greater than or equal to 0.1% to less than or equal to 8% by weight, for example greater than or equal to 0.1% to less than or equal to 5% by weight. This may correspond, for example, to a ratio of 0.2-4g/100ml, for example 1-3g/100ml, based on the pharmaceutical composition. Such a concentration can be achieved without difficulty by the above-mentioned arrangement of the solvent mixture and is particularly advantageous for local pour-on application. In principle, however, concentrations of active ingredient of up to 30% by weight or more are also possible without going beyond the scope of the invention.

Thus, the formulations of the invention are generally liquid and suitable for topical or dermal application, especially as so-called pour-on formulations.

The ectoparasiticidal efficacy of the compositions according to the invention comprising active ingredients from the above groups, in particular fluorinated benzamides, is very effectively provided, especially in the case of the above-mentioned pour-on application. Thus, by using the composition, the amount of active ingredient required can be reduced and the long-term effect can be increased. Thus, their use achieves economic and ecological advantages.

The compositions according to the invention are very suitable for parasite control or parasite prophylaxis. Thus, the pharmaceutical compositions described herein are useful for treating or preventing parasite infestation, in particular for treating or preventing ectoparasites.

The compositions of the invention are particularly suitable for controlling or preventing ectoparasites, preferably ticks and/or mites, and/or flies or fly larvae, and/or lice, on non-human organisms, in particular animals, in particular warm-blooded animals, preferably mammals.

According to one embodiment, the animal may be a domestic animal, such as a caged bird; or mammals, such as hamsters, guinea pigs, rats, mice, chinchillas, ferrets or in particular dogs, cats.

According to another more preferred embodiment, the animal may be an agricultural livestock, including for example poultry, such as turkeys, ducks, geese, and in particular chickens; or preferably mammals, such as sheep, goats, horses, donkeys, camels, buffalos, rabbits, reindeer, fawn deer, in particular cattle and pigs.

According to a particularly preferred embodiment, the composition of the invention is used for controlling and/or preventing ectoparasites in cattle.

Since usually also a certain amount of the composition is spread into the environment of the treated animals, for example by grinding (abrasion) or with debris (debris), the action of the composition of the invention may not only be directed to the animals, but to a corresponding extent to their environment.

As mentioned above, the compositions described herein are preferably suitable for treating or preventing parasite infestation in non-human organisms by instillation or pouring of the composition onto the non-human organism, and are therefore suitable for pour-on application.

Possible parasites that may be mentioned against which the formulations of the invention are effective are:

genera from the order Anoplura, for example, hematophthirius (Haematopinus spp.), phthirius (Linognathus spp.), phlebopus (Solenopots spp.), phillips (Pediculus spp.), phillips spp.).

Genera from the order Mallophaga (Mallophaga), such as louse moubata (Trimenopon spp.), louse (Menopon spp.), ehmenacanthus, louse chews (trichonectines spp.), dalus felis (Felicola spp.), louse (zoophthiris spp.), and buvicola (Bovicola spp.).

Genera from the order Diptera (Diptera), such as, for example, aedes (Aedes spp.), anopheles (Anopheles spp.), culex spp, gnat (Culex spp.), sandfly (Simulium spp.), phlebopus (phlebotomis spp.), lucilia (leucopterus spp.), lucilia (Tabanus spp.), housefly (Musca spp.), gynura (Hydeta spp.), haemaphila (Haematobosma spp.), black horn fly (Haematopia spp.), sting (Stomoxys spp.), manis spp.), lance (Thymus spp.), glossus (Glossina spp.), green (Lucilia spp.), eustis (Lumip), eustis (Lumiphus spp.), eustis (Hypoglossoma spp.), eustis (Memphasium spp.), memphasi (Rhynchus spp.), sphagus spp.), sp spp.). .

Genera from the order Siphonapterida, for example Ctenocephalides spp, ceratophylla spp, ceratophyllus spp, and flea spp. .

Genera from the order metaflumata (metasigmata), such as, for example, the genera Hyalomma, rhipicephalus (Rhipicephalus spp.) (including the genera formerly known as cattle tick (Boophilus)), ixodia (ambyomma spp.), haemanthus (Haemaphysalis spp.), dermanylus (Dermacentor spp.), hard tick (Ixodes spp.), rhipicephalus (Argas spp.), rhipicephalus spp., (Argas spp.), blustus (ornithorhodus spp.), and Rhipicephalus (otosus spp.);

genera from the order of the Mesotigmata, such as Dermanyssus spp, avian Dermanyssus spp, and Pneumonysus spp.

Genera from the order of the Prostigmata (Prostigmata), such as, for example, the genera Hypogaea (Cheyletiella spp.), acarina (Psorergates spp.), hypoderma (Myobia spp.), demodex (Demodex spp.), neotsutsugami (Neotramicilla spp.);

genera from the phylogenous sub-order of Achagata (Astigmata), such as, for example, the genera Dermatophagoides (Acarus spp.), myocopes, primeria (Psoropes spp.), dermatophagoides (Choriopes spp.), eremotes (otodes spp.), sarcophagus (Sarcophages spp.), desmodium (Notoederes spp.), terromophytis (Kneminus spp.), neonectoides (Neonectes spp.), neonectinocoptes (Neonectes spp.), neonectes (Neonectes spp.), cytodia (Cytodites spp.), and Cytodia (Laminosiopsis spp.).

Herein, from the genus diptera, tabanus (Tabanus spp.), musca spp., stropharyngea spp., (Hydrotaea spp.), musca spp., (Haematobia spp.), drosophila spp., (Stomoxys spp.), musca spp., (Glossina spp.), musca spp., (Lucilia spp.) (Calliphora spp.), erythus spp. (Aedes spp.), anopheles spp., (Culex spp.), mulium spp., (Simulium spp.) (phlebotomis spp.); from the genus phylum postarteria, particular preference is given to Hyalomma, rhipicephalus spp (including the genus formerly known as bovine tick (Boophilus), aleyrodida spp (ambroxoma spp.), haemaphystrix spp (Haemaphysalis spp.), dermaphyllus (dermaphanoplor spp.), hard tick (Ixodes spp.), rhynchophyllus spp (Argas spp.), blumea spp., oridiana spp., orithodendron spp., and buthius spp.; of the genera from the order Anoplura, particularly preferred are the genera Haematopinus (Haematopinus spp.), pediculosis (Linogaphus spp.), pediculosis (Solenoptes spp.);

species from the order trichophaga, particularly preferably of the genus zoophthiridae (Damalina spp.), of the genus bovine feather lous (Bovicola spp.), of the genus louse (Trimenopon spp.); of the genera from the order of the Mesotigmata, the genera Dermanyssus spp, and Dermanyssus spp; of the genera derived from the subdivision of the phylogenalea (Astigmata), the genera itch mite (Psoroptes spp.), dermatophagoides (Choroptes spp.), otoacarina (otonectes spp.), sarcoptes (Sarcoptes spp.), and dorsal anal acarina (Notoederes spp.) are particularly preferred.

Mention may be made, as being particularly preferred, of species or genera of arthropods: horn flies (Haematobia irtans), buffalo horn flies (Haematobia irtans exigua), head flies (Hydrotera irtans), autumn flies (Musca autunnalis), culicoides (Culicoides spp.), stinging flies (Stomoxys spp.), glossomyzis (Glossina spp.), aedes (Aedes spp.), anopheles (Anopheles spp.), culex spp.), pediculus bovis (Damalia bovis) (Bovicus), bull Sidae (Linonatus vituli), tabanus bovis (Haematoporus) and Tabanus spp. Calophyllum microphyllum (Solenoptes carpifolius), psoroptes ovis (Psorodes ovis bovis), boophilus microplus (Rhipicephalus microplus), boophilus annulatus (Rhipicephalus annuus), rhipicephalus decorus (Boophilus decorus), rhipicephalus kawakamii (Boophilus), rhipicephalus kawakamii (Ixodes ricinus), haematococcus major (Amblyomma major), callionis carbonisatus (Amblyomma variegatum), ixodes cyclxcapular, haemaphys longicornus (Haemaphys longicornus), erythium auriculatum (Octobus megnini).

The compositions of the invention may be prepared by conventional means, for example by mixing the active ingredient with the other ingredients under agitation to form a solution. This may optionally be filtered. For example, plastic tubes are suitable for filling.

The liquid formulation of the present invention is characterized by its excellent storage stability for at least one year, preferably at least two years, more preferably at least three years in all climatic zones. Due to the very high efficacy, the application rates can be kept low. The preferred volume of administration is 0.01-1ml/kg [ body weight of the animal to be treated ], preferably 0.05-0.1ml/kg [ body weight of the animal to be treated ].

The compositions of the present invention also have excellent skin compatibility and have low toxicity. Finally, they are environmentally friendly due to their biodegradability.

Solubility test

The dissolution experiments of the active ingredients I-1, I-2, I-3 and I-4 in the solvent of the pharmaceutical composition of the present invention are shown below. For biological effects, the active ingredient should be incorporated into the formulation in a dose or amount, ideally it should be in solution in the formulation so that the active ingredient is therefore dissolved in the solvent. Due to the limited volume of application, the solvent requires a certain minimum solubility.

Table 1 shows the results of dissolution experiments for active ingredient I-1. In this case, initially 10g of a suitable solvent or solvent mixture is added and as much active ingredient as possible is added until the solution is saturated. Isopropyl alcohol (IPA) and propylene carbonate (PPC) are used as solvents. The sample was stirred for 3 days. If the active ingredient is completely dissolved, the active ingredient is added again. Subsequently, the samples were stored for a further 4 days at the relevant temperature and centrifuged to remove undissolved particles. The supernatants were analyzed in each case for active ingredient content by HPLC-UV.

Table 1:

as can be seen from table 1, in the single solvents isopropanol and propylene carbonate, the required criteria are not met, in particular in terms of sufficient solubility. An advantageous and particularly preferred desired solubility of the active ingredient according to the invention is in the range of at least 5% m/V, wherein there should be sufficient clearance from the saturation solubility. Unexpectedly, the isopropanol and propylene carbonate mixture showed a significant solubility increase compared to the pure solvent, which is detailed in table 1.

Furthermore, solubility experiments in different solvents of the other three active ingredients selected from the group of fluorinated heteroaryl amides were also performed. The solubility experiment was carried out analogously to the above experiment, however, only at room temperature and with the choice of the solvent mixture isopropanol/propylene carbonate 65% [ m/m ]. The results are shown in Table 2.

Table 2:

it has also been found that very good solubility of the active ingredients of the heteroaryl amides, in particular for the defined structures, for the active ingredients I-2, I-3 and I-4 can be achieved by the solvent mixtures or solvent phases of the compositions of the invention.

It is also shown that the significant increase in solubility is not limited to only mixtures of isopropanol and propylene carbonate, but also shows, among other solvents of the alcohol and carbonate series, as defined above for the first and second solvents.

Table 3:

as is clear from table 3, the use of other solvents can achieve an increase in solubility. Thus, the invention extends to other solvents within the indicated range. Shown herein as examples are embodiments of ethanol and glycerol carbonate, mixtures thereof and combinations thereof with the solvents, isopropanol and propylene carbonate already shown.

Solvent systems were also tested in which the first solvent comprised two alcohols. The results are shown in Table 4.

Table 4:

it can also be shown that this binary system enables good solubility of the active ingredient of formula I-1.

Formulation examples

Described below are preparation examples of formulations comprising the active ingredients I-1, I-2, I-3 and I-4 as defined above and additives. In all embodied examples, the respective active ingredients were completely dissolved and the stability was as desired.

Table 5 herein shows suitable formulation examples comprising data for solvent mixtures, active ingredients and optionally other additives.

Table 5:

table 6 shows formulations that can be prepared according to the solubility test

Formulations numbered 1 to 65 were prepared and good solubility and complete dissolution of the active ingredient was observed.

The experiments numbered 66 to 107 are further prophetic examples where the desired solubility can be predicted based on the solubility experiments performed, the actual examples of the preparation and based on the chemical structure of the active ingredient and the solvent selected.

In vitro and in vivo test examples

Other characteristics and efficacies of the formulations of the invention are described below.

Example 1

Determination of spreading characteristics of a colored placebo formulation on bovine skin

The aim of this in vitro study was to determine the diffusion profile of a coloured placebo formulation (i.e. without active ingredient) on bovine skin. These tests show that the results will be applicable to the spreading effect of the formulations containing the active ingredient. The test was performed using a two-solvent phase consisting of Isopropanol (IPA) and propylene carbonate (PPC).

For this purpose, approximately 10x 10cm skin pieces with the lightest possible coat color were obtained from cattle after slaughter and placed on a hot plate covered with aluminum. The plate was heated to 34 ℃ +/-0.5 ℃. The cut skin and pieces of skin of natural hair length were examined. 0.025% brilliant blue FCF was added as a colorant. The behavior of the formulation on the skin surface and on the spread area was measured within 60 minutes. Spreading was also assessed by a rating system. In this case, such a formulation is particularly advantageous and suitable for later use on animals, since its spreading properties over the observation period achieve a sufficient distribution over the skin patch.

The results are listed in table 7, which shows the spreading characteristics of the colored placebo formulation on skin patches.

Table 7 shows the area occupied by the formulation directly on the skin sample after application and one hour, and also shows the applied formulation volume, the hair length of the hair on the skin and the skin temperature.

Table 7:

it is apparent from the table that the spreading properties are particularly advantageous. The best results were achieved when the ratio of Isopropanol (IPA) to propylene carbonate (PPC) was 65.

Although this test also shows good results with a ratio of Isopropanol (IPA) to propylene carbonate (PPC) of 90.

Table 8:

example 2

In example 2, the spreading and run-off characteristics of the colored placebo formulation on bovine skin were determined. The purpose of this in vitro study was to determine the spreading and run-off characteristics of the colored placebo formulation on bovine skin. 0.025% brilliant blue FCF was added as a colorant.

The formulations used correspond to those in table 8.

For this purpose, a pelt of about 10x 10cm in the lightest possible color was obtained from the cattle after slaughter and placed on a hot plate covered with aluminum. The plate was heated to 34+/-0.5 ℃. For the run-off test, the heating plate was set at an angle of 45 ° +/-2 °. A piece of filter paper was fixed under the skin patch.

The behavior and the run-off rate of the formulation on the skin surface were recorded in video for more than one minute, and then the run-off rate was calculated by passing through a ruler. Spreading was evaluated by a rating system.

In this case, these preparations are particularly suitable for later use on animals, since the leaching behavior during the observation period results in no or only little coloration of the filter paper. The preparation also achieves a sufficient distribution on the skin patch.

The results are shown in table 9, which measures the loss rate of the longest flow trajectory within 1 minute after administration of 750 μ l of the colored placebo formulation.

Table 9:

from these tests it is evident that the tests using Isopropanol (IPA) and propylene carbonate (PPC) in the claimed ratios have provided very good results, since the run-off characteristics during the observation period result in no or only minimal coloration of the filter paper, in which case a sufficient distribution on the skin patch is achieved.

Example 3

In example 3, the efficacy of pour-on formulations against horn flies (Haematobia irritans irritans) on cattle was determined. The purpose of this study was to determine the efficacy of insecticide formulations in preventing experimentally generated ceratitis infestations in cattle.

The study was performed as a blind, negative control, randomized parallel group efficacy study. Each group included 5 animals. All animals were sorted in descending order prior to treatment by fly count, and then 5 animals were grouped into 4 (x) zones. Cattle were randomly assigned to the regions and sorted in ascending order. Cattle were individually tethered in a gauze-enclosed space. Each animal was infested with approximately 200 uneaten flies on days-5, 1, 7, 14, 21, 28, and in some cases on days 35 and 42. The number of flies on the cattle was determined 4 hours after the infection on the first day, 24 hours after the infection on the second day, on days 8, 15, 22, 29 and, if appropriate, on days 36, 43, 50 and 57. Efficacy against fly infestation was determined by comparing the number of flies on treated cattle to the number of flies on untreated cattle. In this case, if at least 90% of the effect is measured in the treated group compared to the control group, the treatment is judged to be successful.

The results are shown in table 10, which illustrates the effect of the formulation of the invention on horn flies on cattle.

Table 10:

dpt = days post treatment

na = no data

As is apparent from table 10, examples 5 and 7 have a long-lasting and effective effect even at low doses. Furthermore, examples 8, 9, 1, 3 and 11 are also durably effective.

Example 4

In example 4, the efficacy of a pour-on formulation against ticks on cattle (Rhipicephalus microplus) was determined.

The objective of this study was to determine the therapeutic and prophylactic efficacy of the acaricide formulations on Boophilus microplus infestation in cattle resulting from the experiments.

The study was conducted as a parallel group, non-blind, negative control, random efficacy study. Each group included 5 animals. All animals were previously sorted in descending order by sex and number of individual ticks infested prior to treatment (days-14 to-2) and then 5 animals were divided into 2 (x) zones. Cattle were randomly assigned to the regions and sorted in ascending order. Each animal was infested with 3000 larvae on days-35, -33, -29, -27, -22, -20, -15, -13, -8, -6, -1, 5, 7, 12, 14, 19, 21, 26, and 28. The dropped, saturated females were collected daily on days-14 to-2 and 0 to 56. Ticks from day-14 to day-2 were used for grouping, ticks from day 1 to day 28 were used to determine the treatment effect, and ticks from day 29 to the end of the tick decline period were used to determine the prophylactic effect. The fertility of ticks was also determined. This was done by evaluating oviposition and larval hatching from pooled samples of congested female ticks. In this case, >60% of the larvae hatch indicates a normal hatchability. The compounds tested here did not achieve significant additional effects.

As for the treatment effect against the existing tick infestation, when 90% effect of the treatment group (based on the number of the female ticks that were lost with blood on days 1 to 28 after the treatment) was measured as compared with the control group, the treatment was judged to be successful. Therefore, if the effect is less than 90%, there is no effect.

For the preventive effect against newly emerging tick infestation, treatment success was judged when 90% effect of the treatment group (based on the number of female ticks that were lost with blood at 29-56 days after treatment) was measured compared to the control group. Therefore, if the effect is less than 90%, a sufficient effect is not exhibited.

The results are shown in tables 11 and 12. Table 11 shows the therapeutic effect of the inventive formulation on cattle at all stages of cattle tick (mini cattle tick), and table 12 shows the prophylactic effect of the inventive formulation on cattle tick (mini cattle tick) infestation occurring on cattle.

Table 11:

na = no data

Table 12:

na = no data

In tables 11 and 12, it can be seen that all active ingredients in the compositions of the invention have a high efficacy for the prevention and treatment of tick infestations, even at low doses.

Example 5

Efficacy of pour-on formulations against ticks on cattle (Bovicola bovis) was determined according to example 5. The purpose of this study was to determine the treatment and prevention efficacy of insecticidal formulations against hair lice infestation naturally occurring in cattle.

The study was conducted as a parallel group, non-blind, negative control efficacy study. Each group included 5 animals. Lice were counted on day-2 and days 2, 14, 28 and 42 prior to treatment. In this case, the hair of each animal was screened at 10 sites and all larvae and adult hair lice stages were counted. The results for each animal were pooled, averaged across a group of animals, and compared to the number of lice in untreated controls. The acute efficacy of the existing hair lice infestation was determined on day 2. In this case, the treatment is judged to be successful if at least 90% of the effect is measured in the treated group compared to the control group. The persistent effectiveness of existing hair lice infestation was measured in counts at days 14, 21 and 42.

In this case, if 100% of the effect is measured in the treatment group compared to the control group, the treatment is judged to be successful. Therefore, in the case where the effect is less than 100%, the treatment is judged to be unsuccessful.

Table 13:

test area	Preparation examples	Dosage mg/kg	dpt 2	dpt 14	dpt 28	dpt 42
							B	2	2	>90	100	100	100
B	12	2	>90	100	100	100
							A	16	3	<90	<100	<100	100
A	13	3	<90	<100	100	100
							A	15	3	<90	<100	100	100

Dpt = days post treatment

Table 13 shows the effect of the formulations of the present invention on hair lice on cattle.

It is evident from table 13 that examples 2 and 16 in particular have a relatively fast high efficacy when they are used in the form of a mixture of the composition according to the invention with the solvent.

It is therefore evident from the foregoing that the pharmaceutically active compositions according to the invention exhibit good solubility for the active ingredients of benzamides and that the use of these enables effective active compositions, in particular for the treatment or prevention of parasite infestation, especially in the case of non-human organisms. In this case, use as a pour-on is particularly advantageous.

Claims

1. A pharmaceutical composition comprising at least one pharmaceutically active ingredient soluble in a solvent phase, wherein the pharmaceutically active ingredient is a fluorinated heteroaryl amide, and wherein the solvent phase is a solvent mixture comprising at least a first solvent and a second solvent different from the first solvent, wherein the first solvent comprises a C1 to C15-alcohol, wherein the second solvent comprises an organic carbonate, wherein the first solvent is present in a proportion of from 50 wt% to 95 wt% and wherein the second solvent is present in a proportion of from 5 wt% to 50 wt%, based on the sum of the solvents in the solvent phase.

2. The pharmaceutical composition according to claim 1, wherein the first solvent is selected from the group consisting of C1-C4-alkanols, optionally substituted with at least one C1-C4-alkoxy or phenyl group, and wherein the first solvent is selected from the group consisting of ethanol, n-propanol, isopropanol, butanol.

3. The pharmaceutical composition according to claim 1 or 2, wherein the second solvent is selected from aliphatic C1-C4-carbonates, optionally substituted with hydroxyl groups.

4. The pharmaceutical composition of claim 2 or 3, wherein the first solvent is isopropanol and the second solvent is propylene carbonate.

5. The pharmaceutical composition of any one of claims 1 to 4, wherein the solvent mixture consists of the first solvent and the second solvent.

6. The pharmaceutical composition according to any one of claims 1 to 4, wherein the solvent mixture contains, in addition to the first solvent and the second solvent, a third solvent different from the first solvent and the second solvent.

7. The pharmaceutical composition of claim 6, wherein the third solvent is selected from the group consisting of water, butylated hydroxytoluene, N-methylpyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, triethyl phosphate, benzyl benzoate, octyldodecanol, paraffin, triglycerides, propylene glycol caprylic decanoate, glycol ethers.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the second solvent is present in an amount of ≥ 20% by weight to ≤ 45% by weight, preferably in an amount of ≥ 30% by weight to ≤ 40% by weight, based on the sum of the solvents in the solvent mixture.

9. Pharmaceutical composition according to any one of claims 1 to 8, characterized in that the active ingredient is selected from compounds of general formula (I), and salts, N-oxides and tautomeric forms of the compounds of formula (I):

wherein

R ¹ Is H, in each case optionally substituted C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₆ -alkylcarbonyl group, C ₁ -C ₆ Alkoxycarbonyl, aryl- (C) ₁ -C ₃ ) -alkyl, heteroaryl-(C ₁ -C ₃ ) -alkyl, or optionally substituted C ₁ -C ₆ -alkyl, preferably H or preferably C ₁ -C ₂ Alkyl, very particularly preferably H or methyl, in particular H,

these sections are as follows:

A ₁ is CR ² Or the number of N is greater than the number of N,

A ₂ is CR ³ Or the number of N is greater than the number of N,

A ₃ is CR ⁴ Or the number of N is greater than the number of N,

A ₄ is CR ⁵ Or the number of N is greater than the number of N,

B ₁ is CR ⁶ Or the number of N is greater than the number of N,

B ₂ is CR ⁷ Or the number of the N-substituted aryl groups,

B ₃ is CR ⁸ Or the number of the N-substituted aryl groups,

B ₄ is CR ⁹ Or N, and

B ₅ is CR ¹⁰ Or the number of the N-substituted aryl groups,

R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁹ and R ¹⁰ Each, independently of the others, being H, halogen, cyano, nitro, in each case optionally substituted C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₆ Alkoxy, N-C ₁ -C ₆ -alkoxyimino-C ₁ -C ₃ Alkyl radical, C ₁ -C ₆ Alkyl sulfanyl, C ₁ -C ₆ -alkylsulfinyl, C ₁ -C ₆ -alkylsulfonyl, N-C ₁ -C ₆ Alkylamino, N-di-C ₁ -C ₆ Alkylamino or N-C ₁ -C ₃ -alkoxy-C ₁ -C ₄ -alkylamino or 1-pyrrolidinyl;

if A is ₂ And A ₃ All moieties are not N, then R ³ And R ⁴ May be taken together with the carbon atom to which they are bonded to form a compound containing 0, 1 or 2 nitrogen atoms and/or 0 or 1A 5-or 6-membered ring of oxygen atoms and/or 0 or 1 sulfur atoms; or

If A is ₁ And A ₂ All moieties are not N, then R ² And R ³ May form together with the carbon atom to which they are bonded a 6-membered ring containing 0, 1 or 2 nitrogen atoms;

R ⁸ is halogen, cyano, nitro, in each case optionally substituted C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₆ Alkoxy, N-C ₁ -C ₆ -alkoxyimino-C ₁ -C ₃ Alkyl radical, C ₁ -C ₆ Alkyl sulfanyl, C ₁ -C ₆ -alkylsulfinyl, C ₁ -C ₆ -alkylsulfonyl, N-C ₁ -C ₆ Alkylamino or N, N-di-C ₁ -C ₆ -an alkylamino group;

w is O or S, and W is O or S,

q is H, formyl, hydroxy, amino or in each case optionally substituted C ₁ -C ₆ -an alkyl group; c ₂ -C ₆ -an alkenyl group; c ₂ -C ₆ -an alkynyl group; c ₃ -C ₆ -a cycloalkyl group; c ₁ -C ₅ -a heterocycloalkyl group; c ₁ -C ₄ -an alkoxy group; c ₁ -C ₆ -alkyl-C ₃ -C ₆ -a cycloalkyl group; c ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -an alkyl group; c ₆ -、C ₁₀ -C ₁₄ -an aryl group; c ₁ -C ₅ -a heteroaryl group; c ₆ -、C ₁₀ -、C ₁₄ -aryl- (C) ₁ -C ₃ ) -an alkyl group; c ₁ -C ₅ -heteroaryl- (C) ₁ -C ₃ ) -an alkyl group; N-C ₁ -C ₄ -an alkylamino group; N-C ₁ -C ₄ -alkylcarbonylamino or N, N-di-C ₁ -C ₄ -an alkylamino group; or

Is an optionally poly-V-substituted unsaturated 6-membered carbocyclic ring; or alternatively

Is an optionally poly-V-substituted unsaturated 4-, 5-or 6-membered heterocyclic ring, wherein

V independently of one another is halogen, cyano, nitro, in each caseC optionally substituted in each case ₁ -C ₆ Alkyl radical, C ₁ -C ₄ -alkenyl, C ₁ -C ₄ -alkynyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₆ Alkoxy, N-C ₁ -C ₆ -alkoxyimino-C ₁ -C ₃ Alkyl radical, C ₁ -C ₆ Alkyl sulfanyl, C ₁ -C ₆ -alkylsulfinyl, C ₁ -C ₆ -alkylsulfonyl or N, N-di- (C) ₁ -C ₆ -alkyl) amino;

10. The pharmaceutical composition according to claim 9, wherein the active ingredient is selected from the group consisting of:

11. the pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutically active ingredient is present in an amount of greater than or equal to 0.1% to less than or equal to 5% by weight.

12. The pharmaceutical composition according to any one of claims 1 to 11, for use in the treatment or prevention of a parasitic infestation.

13. The pharmaceutical composition according to claim 12, for use in the treatment or prevention of ectoparasite infestation.

14. The pharmaceutical composition according to any one of claims 1 to 13, for use in the treatment or prevention of a parasitic infestation in a non-human organism.

15. The pharmaceutical composition according to claim 14 for use in treating or preventing parasite infestation in a non-human organism by instilling or pouring the composition onto the non-human organism.